Chen et al. BMC Ophthalmology (2017) 17:83 DOI 10.1186/s12886-017-0470-y
RESEARCH ARTICLE
Open Access
Serum uric acid concentration is associated with hypertensive retinopathy in hypertensive chinese adults Xuling Chen1, Ying Meng1, Jun Li1, Hiacheng She2, Liang Zhao1, Jing Zhang1, Yuan Peng1, Kun Shang1, Yadi Zhang1, Xiaopeng Gu1, Wenbin Yang3, Yan Zhang4, Jianping Li4, Xianhui Qin5, Binyan Wang5, Xiping Xu5, Fanfan Hou5, Genfu Tang6, Rongfeng Liao3,7, Yong Huo4* and Liu Yang1*
Abstract Background: This cross sectional investigation included 12,966 subjects with hypertension, a cohort of the China Stroke Primary Prevention Trial (CSPPT), a randomized, multicenter clinical trial. This study aimed to explore the correlation between serum uric acid (SUA) concentration and hypertensive retinopathy in hypertensive adults. Methods: Diagnosis of hypertensive retinopathy was determined by non-mydriatic fundus photography and classified with Keith-Wagener-Barker (KWB) system. The correlation of SUA levels with hypertensive retinopathy prevalence and severity was assessed by statistical analysis. Results: 9848 (75.95%) subjects were diagnosed with hypertensive retinopathy with the following retinopathy grade distribution: grade 1: 58.80%, grade 2: 14.81%, and grade 3–4: 2.34%. SUA levels were significantly associated with hypertensive retinopathy prevalence. Patients with hypertensive retinopathy had higher SUA levels than those without hypertensive retinopathy. Patients in the highest uric acid quartile had an odds ratio for hypertensive retinopathy of 1.21 compared to patients in the lowest uric acid quartile (OR = 1.21, 95% CI: 1.05–1.40, P = 0.008). When compared to the non-hyperuricemia group, those in the hyperuricemia group had an odds ratio for hypertensive retinopathy of 1.18(OR = 1.18, 95% CI: 1.05–1.33, P = 0.004). Every 1 mg/dl increase in uric acid concentration was significantly associated with a 6% higher odds of hypertensive retinopathy (OR = 1.06, 95% CI: 1.02–1.10, P = 0.002). Conclusions: The prevalence of hypertensive retinopathy was high (75.95%) among hypertensives in our patients cohort. In addition, SUA concentration was significantly associated with hypertensive retinopathy. Keywords: Serum Uric Acid Concentration, Hypertensive Retinopathy, Hypertension, Hyperuricemia, Keith-WagenerBarker system
Background Hypertension affects more than 330 million people in China, it is the most common chronic disease in the Chinese population [1]. Hypertensive retinopathy (HR) is one of the micro vascular complications of hypertension with an insidious onset, which, if left untreated, can * Correspondence: [email protected]; [email protected] 4 Department of Cardiology, Peking University First Hospital, No.8 Xishiku Street, Xicheng District, Beijing 100034, China 1 Department of Ophthalmology, Key Laboratory of Vision Loss and Restoration, Ministry of Education, Peking University First Hospital, No.8 Xishiku Street, Xicheng District, Beijing 100034, China Full list of author information is available at the end of the article
possibly open the way for retinal vascular obstruction (RVO), retinal thrombus, ischemic optic neuropathy (ION) and vitreous hemorrhage [2, 3]. Furthermore, the retinal vascular bed, the only vascular bed that can be observed by non-invasive procedures in vivo, is regarded as an essential indicator to evaluate the status of systemic microvasculature [4]. Many studies have proved the value of the retinal vascular in predicting the severity of target organ damage, including cardiovascular, renal and cerebrovascular disease [5, 6]. The prevalence of HR in hypertensive patients varied among different researches (30.6%–94.6%) [7–9]. To date there
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Chen et al. BMC Ophthalmology (2017) 17:83
has been no large sample, epidemiologic statistical reports on HR in China. Some studies have explored the risk factors for HR, including endothelial dysfunction [10], oxidative stress [11], and low-grade systemic inflammation [12]. However, other risk factors, such as serum triglyceride levels, serum uric acid (SUA) and metabolic syndrome, have been studied with relatively inconclusive results. Uric acid is the final product of purine metabolism in humans. Hyperuricemia is a predisposing condition for gout and is linked with metabolic syndrome [13], resulting from increased production of uric acid coupled with excretion dysfunction. It was also regarded as an independent risk factor for hypertension. Two meta-analysis of published prospective studies showed that the overall risk for incident hypertension increased by 13% and 15% per 1 mg/dl increase in SUA level respectively [14, 15]. Numerous studies have suggested that SUA is correlated with some ocular diseases [16], especially diabetic retinopathy [17]. Our study sought to characterize epidemiological features of HR and investigate the association between SUA and HR. We were interested whether SUA is an independent risk factor contributing to HR.
Methods Study design and participants
All subjects in this study came from the China Stroke Primary Prevention Trial (CSPPT), conducted from May 19, 2008, to August 24, 2013, in 32 communities in the Jiangsu and Anhui provinces of China [18]. The study complied with the Helsinki Declaration and was approved by the Ethics Committee of the Institute of Biomedicine, Anhui Medical University, Hefei, China (FWA assurance number FWA00001263). All participants provided written informed consent. CSPPT study was a large communitybased, randomized, multicenter, double blind, and actively controlled trial designed to evaluate whether combination therapy with enalapril maleate and folic acid tablets combined were more effective in preventing stroke in Chinese adults with hypertension than enalapril maleate alone. Details of the trial have been described elsewhere (http:// clinicaltrials.gov/ct2/show/NCT00794885). Our study included a total of 20,702 hypertensive subjects, 13,140 had fundus picture, among them, and 155 subjects were excluded for difficult gradable fundus photographs, for the reason of serious opacity of refractive media or terrible fixation vision. After excluding 7736 subjects who were missing either gradable fundus photographs or analysis of SUA, a total of 12,966 subjects were analyzed.
Page 2 of 10
(Topcon TRC-NW8 Non-Mydriatic Retinal Camera, Canon CR-2 AF Non-Mydriatic Retinal Camera and Kowa nonmyd 7 Fundus Camera). All the photographs were randomly evaluated by four professional ophthalmologists with double mask, and we ensured the results of science and reliability through good consistency checks (kappa between 0.71–0.95). HR was classified into grades 1–4 according to the Keith-Wagener-Barker (KWB) system (for details of classification see [19] Table 1). Laboratory Examinations
Laboratory examinations were performed at the core lab of the National Clinical Research Center for Kidney Disease (Nanfang Hospital, Guangzhou, China). Fasting serum uric acid (SUA), lipids (serum total cholesterol, high density lipoprotein – HDL-C, and triglycerides), serum creatinine, blood glucose and homocysteine were measured by using automatic clinical analyzers (Beckman Coulter), serum folic acid were measured by using a chemiluminescent immunoassay (New Industrial). Diabetes mellitus (DM) was defined as a fasting plasma glucose concentration greater than or equal to 7.0 mmol/l, or a history of diabetes paired with the use of an oral antidiabetic drug. Hyperuricemia was defined as serum uric acid exceeding 7.0 mg/dl in males and 6.0 mg/dl in females. Demographic data
All participants were interviewed using a standardized questionnaire including age, gender, sociodemographic status, education, occupation, diet, lifestyle, health behavior, medical history and personal history including smoking status, alcohol consumption, and known systemic disease. Current smoking was defined as smoking one cigarette per day for at least half a year. Current drinking was defined as drinking once per week for at least half a year. Anthropometric measurements were taken according to a standard operating procedure. Body Mass Index (BMI) was calculated as weight (kilograms) divided by height (meters) squared. Table 1 The Keith–Wagener–Barker classification system for hypertensive retinopathy Grade
No detectable positive signs
1
Mild or moderate generalized retinal arteriolar narrowing, arteriovenous tortuosity
2
Definite focal narrowing and arteriovenous nipping, crossing compression
3
Copper wire or silver wire artery, signs of grade 2 retinopathy plus retinal hemorrhages, exudates and cotton wool spots
4
Severe grade 3 retinopathy plus papilledema or retinal edema
Classification of Hypertensive Retinopathy
Non-mydriatic fundus photographs were taken in the posterior pole and macula-centered, using fundus cameras
Features
None
Chen et al. BMC Ophthalmology (2017) 17:83
Blood Pressure (BP) measurements
Systolic and diastolic BP (SBP/DBP mmHg) was measured after subjects resting for 30 min; participants were seated with their right arms supported at the level of the heart for BP measurements. BP was measured using a mercury sphygmomanometer with an appropriate cuff size, and recorded as the mean of three measurements, with one-minute intervals between each. Hypertension was defined as a BP greater than or equal to 140 mmHg systolic and/or 90 mmHg diastolic. Statistical analysis
All analyses were performed using Empower Stats statistical software (http://www.empowerstats.com, X&Y Solutions, Inc. Boston, MA) and the statistical package R(http://www.r-project.org). Data were presented as frequencies (percentages) for categorical variables and means ± standard deviation (SD) for continuous variables. Stratified analysis, interaction tests, and covariate screening were performed. Binary logistic regression analyses were used to assess the associations between HR (as a binary variable) and SUA concentration. SUA was evaluated as a continuous variable, a bi-level classification variable (Non-hyperuricemia: SUA
RESEARCH ARTICLE
Open Access
Serum uric acid concentration is associated with hypertensive retinopathy in hypertensive chinese adults Xuling Chen1, Ying Meng1, Jun Li1, Hiacheng She2, Liang Zhao1, Jing Zhang1, Yuan Peng1, Kun Shang1, Yadi Zhang1, Xiaopeng Gu1, Wenbin Yang3, Yan Zhang4, Jianping Li4, Xianhui Qin5, Binyan Wang5, Xiping Xu5, Fanfan Hou5, Genfu Tang6, Rongfeng Liao3,7, Yong Huo4* and Liu Yang1*
Abstract Background: This cross sectional investigation included 12,966 subjects with hypertension, a cohort of the China Stroke Primary Prevention Trial (CSPPT), a randomized, multicenter clinical trial. This study aimed to explore the correlation between serum uric acid (SUA) concentration and hypertensive retinopathy in hypertensive adults. Methods: Diagnosis of hypertensive retinopathy was determined by non-mydriatic fundus photography and classified with Keith-Wagener-Barker (KWB) system. The correlation of SUA levels with hypertensive retinopathy prevalence and severity was assessed by statistical analysis. Results: 9848 (75.95%) subjects were diagnosed with hypertensive retinopathy with the following retinopathy grade distribution: grade 1: 58.80%, grade 2: 14.81%, and grade 3–4: 2.34%. SUA levels were significantly associated with hypertensive retinopathy prevalence. Patients with hypertensive retinopathy had higher SUA levels than those without hypertensive retinopathy. Patients in the highest uric acid quartile had an odds ratio for hypertensive retinopathy of 1.21 compared to patients in the lowest uric acid quartile (OR = 1.21, 95% CI: 1.05–1.40, P = 0.008). When compared to the non-hyperuricemia group, those in the hyperuricemia group had an odds ratio for hypertensive retinopathy of 1.18(OR = 1.18, 95% CI: 1.05–1.33, P = 0.004). Every 1 mg/dl increase in uric acid concentration was significantly associated with a 6% higher odds of hypertensive retinopathy (OR = 1.06, 95% CI: 1.02–1.10, P = 0.002). Conclusions: The prevalence of hypertensive retinopathy was high (75.95%) among hypertensives in our patients cohort. In addition, SUA concentration was significantly associated with hypertensive retinopathy. Keywords: Serum Uric Acid Concentration, Hypertensive Retinopathy, Hypertension, Hyperuricemia, Keith-WagenerBarker system
Background Hypertension affects more than 330 million people in China, it is the most common chronic disease in the Chinese population [1]. Hypertensive retinopathy (HR) is one of the micro vascular complications of hypertension with an insidious onset, which, if left untreated, can * Correspondence: [email protected]; [email protected] 4 Department of Cardiology, Peking University First Hospital, No.8 Xishiku Street, Xicheng District, Beijing 100034, China 1 Department of Ophthalmology, Key Laboratory of Vision Loss and Restoration, Ministry of Education, Peking University First Hospital, No.8 Xishiku Street, Xicheng District, Beijing 100034, China Full list of author information is available at the end of the article
possibly open the way for retinal vascular obstruction (RVO), retinal thrombus, ischemic optic neuropathy (ION) and vitreous hemorrhage [2, 3]. Furthermore, the retinal vascular bed, the only vascular bed that can be observed by non-invasive procedures in vivo, is regarded as an essential indicator to evaluate the status of systemic microvasculature [4]. Many studies have proved the value of the retinal vascular in predicting the severity of target organ damage, including cardiovascular, renal and cerebrovascular disease [5, 6]. The prevalence of HR in hypertensive patients varied among different researches (30.6%–94.6%) [7–9]. To date there
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Chen et al. BMC Ophthalmology (2017) 17:83
has been no large sample, epidemiologic statistical reports on HR in China. Some studies have explored the risk factors for HR, including endothelial dysfunction [10], oxidative stress [11], and low-grade systemic inflammation [12]. However, other risk factors, such as serum triglyceride levels, serum uric acid (SUA) and metabolic syndrome, have been studied with relatively inconclusive results. Uric acid is the final product of purine metabolism in humans. Hyperuricemia is a predisposing condition for gout and is linked with metabolic syndrome [13], resulting from increased production of uric acid coupled with excretion dysfunction. It was also regarded as an independent risk factor for hypertension. Two meta-analysis of published prospective studies showed that the overall risk for incident hypertension increased by 13% and 15% per 1 mg/dl increase in SUA level respectively [14, 15]. Numerous studies have suggested that SUA is correlated with some ocular diseases [16], especially diabetic retinopathy [17]. Our study sought to characterize epidemiological features of HR and investigate the association between SUA and HR. We were interested whether SUA is an independent risk factor contributing to HR.
Methods Study design and participants
All subjects in this study came from the China Stroke Primary Prevention Trial (CSPPT), conducted from May 19, 2008, to August 24, 2013, in 32 communities in the Jiangsu and Anhui provinces of China [18]. The study complied with the Helsinki Declaration and was approved by the Ethics Committee of the Institute of Biomedicine, Anhui Medical University, Hefei, China (FWA assurance number FWA00001263). All participants provided written informed consent. CSPPT study was a large communitybased, randomized, multicenter, double blind, and actively controlled trial designed to evaluate whether combination therapy with enalapril maleate and folic acid tablets combined were more effective in preventing stroke in Chinese adults with hypertension than enalapril maleate alone. Details of the trial have been described elsewhere (http:// clinicaltrials.gov/ct2/show/NCT00794885). Our study included a total of 20,702 hypertensive subjects, 13,140 had fundus picture, among them, and 155 subjects were excluded for difficult gradable fundus photographs, for the reason of serious opacity of refractive media or terrible fixation vision. After excluding 7736 subjects who were missing either gradable fundus photographs or analysis of SUA, a total of 12,966 subjects were analyzed.
Page 2 of 10
(Topcon TRC-NW8 Non-Mydriatic Retinal Camera, Canon CR-2 AF Non-Mydriatic Retinal Camera and Kowa nonmyd 7 Fundus Camera). All the photographs were randomly evaluated by four professional ophthalmologists with double mask, and we ensured the results of science and reliability through good consistency checks (kappa between 0.71–0.95). HR was classified into grades 1–4 according to the Keith-Wagener-Barker (KWB) system (for details of classification see [19] Table 1). Laboratory Examinations
Laboratory examinations were performed at the core lab of the National Clinical Research Center for Kidney Disease (Nanfang Hospital, Guangzhou, China). Fasting serum uric acid (SUA), lipids (serum total cholesterol, high density lipoprotein – HDL-C, and triglycerides), serum creatinine, blood glucose and homocysteine were measured by using automatic clinical analyzers (Beckman Coulter), serum folic acid were measured by using a chemiluminescent immunoassay (New Industrial). Diabetes mellitus (DM) was defined as a fasting plasma glucose concentration greater than or equal to 7.0 mmol/l, or a history of diabetes paired with the use of an oral antidiabetic drug. Hyperuricemia was defined as serum uric acid exceeding 7.0 mg/dl in males and 6.0 mg/dl in females. Demographic data
All participants were interviewed using a standardized questionnaire including age, gender, sociodemographic status, education, occupation, diet, lifestyle, health behavior, medical history and personal history including smoking status, alcohol consumption, and known systemic disease. Current smoking was defined as smoking one cigarette per day for at least half a year. Current drinking was defined as drinking once per week for at least half a year. Anthropometric measurements were taken according to a standard operating procedure. Body Mass Index (BMI) was calculated as weight (kilograms) divided by height (meters) squared. Table 1 The Keith–Wagener–Barker classification system for hypertensive retinopathy Grade
No detectable positive signs
1
Mild or moderate generalized retinal arteriolar narrowing, arteriovenous tortuosity
2
Definite focal narrowing and arteriovenous nipping, crossing compression
3
Copper wire or silver wire artery, signs of grade 2 retinopathy plus retinal hemorrhages, exudates and cotton wool spots
4
Severe grade 3 retinopathy plus papilledema or retinal edema
Classification of Hypertensive Retinopathy
Non-mydriatic fundus photographs were taken in the posterior pole and macula-centered, using fundus cameras
Features
None
Chen et al. BMC Ophthalmology (2017) 17:83
Blood Pressure (BP) measurements
Systolic and diastolic BP (SBP/DBP mmHg) was measured after subjects resting for 30 min; participants were seated with their right arms supported at the level of the heart for BP measurements. BP was measured using a mercury sphygmomanometer with an appropriate cuff size, and recorded as the mean of three measurements, with one-minute intervals between each. Hypertension was defined as a BP greater than or equal to 140 mmHg systolic and/or 90 mmHg diastolic. Statistical analysis
All analyses were performed using Empower Stats statistical software (http://www.empowerstats.com, X&Y Solutions, Inc. Boston, MA) and the statistical package R(http://www.r-project.org). Data were presented as frequencies (percentages) for categorical variables and means ± standard deviation (SD) for continuous variables. Stratified analysis, interaction tests, and covariate screening were performed. Binary logistic regression analyses were used to assess the associations between HR (as a binary variable) and SUA concentration. SUA was evaluated as a continuous variable, a bi-level classification variable (Non-hyperuricemia: SUA
